Zwitterionic Polymer-Decorated Lipid Nanoparticles for mRNA Delivery in Mammalian Cells

Abstract

Lipid nanoparticles (LNPs) play a key role in the effective transport of mRNA into cells for protein translation. Despite the stealthiness of poly­(ethylene glycol) (PEG) that helps protect LNPs from protein absorption and blood clearance, the generation of anti-PEG antibodies resulting in PEG allergies remains a challenge for the development of an mRNA vaccine. Herein, a non-PEG lipid was developed by conjugating 1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine (DPPE) with an antifouling zwitterionic polymer, poly­(2-methyacryloyloxyethyl phosphorylcholine) (PMPC), of different chain lengths. The PMPC-LNPs formulated from DPPE-PMPC were spherical (diameter ≈ 144–255 nm), neutral in charge, and stable at 4 °C for up to 28 days. Their fraction of stealthiness being close to 1 emphasized the antifouling characteristics of PMPC decorated on LNPs. The PMPC-LNPs were nontoxic to HEK293T cells, did not induce inflammatory responses in THP-1 cells, and exhibited an mRNA transfection efficiency superior to that of PEG-LNPs. This work demonstrated the potential of the developed zwitterionic polymer-conjugated LNPs as promising mRNA carriers.

Polymer Brushes on Nanoparticles for Controlling the Interaction with Protein-Rich Physiological Media

“…Moreover, the introduction of additional charged groups into SB-coated NPs led to protein aggregation, where the addition of neutral moieties such as biotin preserved the antifouling ability . Nevertheless, ZI polymethacrylates with PC functionalities in the side chains were recently conjugated to lipids to form LNPs that demonstrated stealth behavior and long-term stability in FBS solutions …”